Lens crystallins are long-lived proteins and are therefore subject to post-synthetic modifications. With aging, protein solubility decreases and protein-bound yellow color and fluorescence increase. These changes are greatly accelerated in certain types of cataracts. Despite extensive efforts, the structure and therefore the mechanism of formation of the pigments, which are believed to act in part as protein crosslinks, remain unknown. We have recently shown that prolonged incubation of lens crystallins with reducing sugars led to the formation or pigmented and fluorescent protein adducts and crosslinks similiar to those reported in senile, and cataractous lenses. This process, called nonenzymatic browning or Maillard reaction, is due to the rearrangement of the sugar portion of glycosylated proteins (Amadori products), thus generating highly reactive carbonyl compounds which are responsible for protein pigmentation and crosslinking. Our objective is to investigate the role of the browning reaction in the formation of pigments and crosslinks in crystallins of normal and cataractous lenses. Preliminary data indicate that in nuclear cataract and brunescent lenses there are several fluorescent, yellow and borohydride-reducible protein adducts which co-chromatograph with the synthetic browning products of lysyl residues and glucose. We will purify these compounds, elucidate their structure and identify proteins with which they are associated. In addition, we will investigate the participation of glycolytic intermediates, such as dihydroxyacetone phosphate and glyceraldehyde phosphate in pigment and crosslink formation. This is particularly important since enzymes involved in their metabolism are markedly decreased in senile and cataractous lenses. Finally, we will investigate the potential of nonenzymatic browning compounds to act as photosensitizers which are known to cause superoxide radical mediated damage to lens crystallins. At the present time, too little is known of the role of the browning reaction in aging and cataract formation to formulate precise long-term objectives. However, we anticipate that future research will be aimed at a better understanding of the factors which control the browning rate such as water activity, oxygen, endogenous or exogenous inhibitors.